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Novel composition

a composition and composition technology, applied in the field of new compositions, can solve the problems of structural degradation, loss of biological activity, and unstable therapeutics

Pending Publication Date: 2022-03-17
ARECOR LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides an aqueous solution composition that includes: terlipressin or a salt thereof, one or more buffers, an amino acid, and a tonicity modifier. The buffers are present in the composition at a concentration of 0-5 mM. The composition has a pH of 4.0 to 6.0. The technical effect of this invention is to provide a stable and effective composition for use in various applications such as medical diagnostics and biological research.

Problems solved by technology

When formulated as aqueous solutions, such peptides therapeutics tend to be unstable and are susceptible to structural degradation and consequent loss of biological activity while stored.

Method used

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Examples

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examples

General Methods

[0176](a) Reversed-Phase Chromatography (RP-HPLC)

[0177]High performance reverse phase chromatography was performed using the Waters ACQUITY H-class Bio UPLC® system with a 1.7 μm Ethylene Bridged Hybrid particle, 130 Å pore resin trifunctionally immobilised with a C18 ligand in a 50 mm by 15 2.1 mm column. Mobile Phase A was 0.1 M Na3PO4 adjusted to pH 3.0 using trifluoroacetic acid. Mobile Phase B was prepared by mixing 2 parts (v / v) of acetonitrile with 1 part (v / v) of Mobile Phase A. The sample comprising a formulated peptide was bound in Mobile Phase A and eluted using a gradient of Mobile Phase A and Mobile Phase B. The sample volume was 10 μl, the flow rate was 0.4 mL / min, with 214 nm UV detection. All analyses were performed at 60° C.

[0178](b) Visual Assessment

[0179]Visible particles are suitably detected using the 2.9.20. European Pharmacopoeia Monograph (Particulate Contamination: Visible Particles). The apparatus required consists of a viewing station compri...

formulation examples

[0191]The following example formulations may be prepared:

Example A:Terlipressin acetate100μg / mlSodium succinate1mMSodium chloride150mMWaterqspH adjusted to 5.0Example B:Terlipressin acetate100μg / mlSodium succinate3mMSodium chloride150mMWater for injectionqspH adjusted to 5.0Example C:Terlipressin acetate100μg / mlSodium succinate4.5mMSodium chloride150mMWater for injectionqspH adjusted to 5.0Example D:Terlipressin acetate100μg / mlSodium succinate3mMSodium chloride140mMGlycine10mMWater for injectionqspH adjusted to 5.0Example E:Terlipressin acetate100μg / mlSodium benzoate1mMSodium chloride150mMWater for injectionqspH adjusted to 5.0Example F:Terlipressin acetate100μg / mlSodium benzoate3mMSodium chloride150mMWater for injectionqspH adjusted to 5.0Example G:Terlipressin acetate100μg / mlSodium benzoate4.5mMSodium chloride150mMWater for injectionqspH adjusted to 5.0Example H:Terlipressin acetate100μg / mlSodium benzoate3mMSodium chloride140mMGlycine10mMWater for injectionqspH adjusted to 5.0Exam...

example 2

Buffer Concentration on Stability of Terlipressin

[0195]The effect of buffer concentration on the rate of impurity formation in compositions of terlipressin (as acetate) was investigated using the RP-HPLC method described in General Methods, following storage at 40° C. and 50° C. The effect was investigated in the presence of mannitol (300 mM) and in the presence of sodium chloride (150 mM) as tonicity modifiers. Three buffers were tested: acetate, citrate and lactate. The pH of all compositions was 4.5. The results are shown in Table 1.

TABLE 1Increase in impurity level in compositions of terlipressin following storage at40° C. and 50° C. All compositions were adjusted to pH 4.5.Increase in % impurityExample.AcetatecitratelactateMannitolNaCl40° C.40° C.50° C.50° C.No.(mM)*(mM)(mM)(mM)(mM)(2 weeks)(4 weeks)(2 weeks)(4 weeks)2-10.23000.070.260.431.202-213000.100.320.531.332-333000.170.360.681.592-44.53000.180.370.721.592-553000.210.500.771.832-6103000.260.710.942.142-7203000.380.901.27...

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Abstract

The invention provides inter alia an aqueous solution composition of pH in the range 4.0-6.0 comprising: —terlipressin or a salt thereof; —optionally one or more buffers being substances having at least one ionisable group with a pKa in the range 3.0 to 7.0 and which pKa is within 1 pH unit of the pH of the composition; —optionally an amino acid; and—optionally a tonicity modifier wherein the buffers are present in the composition at a total concentration of 0-5 mM.

Description

[0001]This invention relates to aqueous solution compositions of terlipressin, at low buffer concentrations.BACKGROUND[0002]Terlipressin is a synthetic analogue of vasopressin, a peptide hormone which has important antidiuretic and vasopressor actions and a variety of other actions including glycogenolysis. Terlipressin is used as a vasoactive drug in the management of low blood pressure, and is also used to treat norepinephrine-resistant septic shock, bleeding oesophageal varices, and in the treatment of hepatorenal syndrome. Terlipressin is generally administered via intravenous (IV) injection.[0003]Terlipressin is a cyclic peptide, the structure of which is shown in FIG. 1. When formulated as aqueous solutions, such peptides therapeutics tend to be unstable and are susceptible to structural degradation and consequent loss of biological activity while stored. The structural degradation is typically chemical in nature, including hydrolytic cleavage, cyclic imide formation, isomeriz...

Claims

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Application Information

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IPC IPC(8): A61K38/095A61K47/12A61K47/18A61K47/02A61K47/20A61K47/22A61K47/26
CPCA61K38/095A61K47/12A61K47/183A61K47/26A61K47/20A61K47/22A61K47/02A61K9/0019A61K9/08A61P9/14A61P7/12
Inventor JEZEK, JANGERRING, DAVIDHOWELL, SARAHPINTO, JORGE
Owner ARECOR LTD
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